Chronic fatigue syndrome (CFS) is a complex disorder, defined by the international Fukuda criteria (Fukuda K, et al., The chronic fatigue syndrome: a comprehensive approach to its definition and study, Ann Intern Med. 1994; 121: 953-959) under the supervision of the Atlanta Center for Disease Control (CDC). According to these criteria, the diagnosis of CFS is based on two major criteria being met and the coexistence of a minimum of four minor criteria.
Major Criteria
1. Persistent physical and mental fatigue for at least six months, or of an intermittent character, of new or definite onset, which does not result from recent efforts, is not alleviated by rest, and gets worse with activity, and which causes a substantial reduction in the patient's previous levels of daily activity, which ultimately the patient cannot overcome.
2. Exclusion of other disorders which may potentially cause chronic fatigue, such as endocrine, infectious, neoplastic and/or psychiatric disorders.
Minor Criteria
Four or more of the following minor criteria must be present concurrently, all lasting for six months or more after the presentation of fatigue:                Impairment in concentration or short-term memory.        Odynophagia.        Painful cervical or axillary adenopathies.        Myalgia.        Polyarthralgia with no signs of inflammation.        Headaches of recent onset or with characteristics different from usual.        Unrefreshing sleep.        Post-exertion malaise lasting more than 24 hours.        
Among the disorders that may be confused with CFS is fibromyalgia (FM), which is a syndrome characterised by symptoms of chronic generalised musculoskeletal pain that is not articular in origin. According to the classification criteria of the American College of Rheumatology (The American College of Rheumatology, 1990, Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee, Arthritis Rheum 1990; 33(2): 160-172) the two basic characteristics for the diagnosis of FM are:
1) the presence of generalised pain lasting over three months;
2) abnormal sensitivity to digital pressure of approximately 4 kg in at least 11 of 18 specific points, known as “tender points”. Besides pain, patients with FM experience some of the following symptoms: sleep disorders, irritable bowel syndrome, ankylosis and stiffness, head or face aches, abdominal malaise, irritable bladder, paraesthesia, numbness or itching, chest pains and costochondralgia (muscle pain where the ribs join the sternum), dizziness and nausea, etc. Symptoms tend to fluctuate and do not necessarily occur simultaneously.
FM and CFS are two different disorders but with very similar presentation and symptoms, this frequently confusing non-experts, despite which, they may coexist in many patients. Almost 80% of CFS sufferers meet the FM classification criteria, although only 7 to 10% of patients with FM meet those for CFS. Differential diagnosis between the two and eliminating other possible causes of pain and fatigue is fundamental for a correct diagnostic, prognostic and therapeutic approach.
CFS predominantly affects young adults with an onset peak between 20 and 40 years. It is 2-3 times more common in women than in men (Lloyd A R, et al., Prevalence of chronic fatigue syndrome in an Australian population, Med J August 1990; 153: 522-528), although this ratio may be due to women seeking medical care at all levels more frequently (Henderson A S., Care-eliciting behavior in man, J Nery Ment Dis 1974; 159: 172-181).
The prevalence of CFS in the population is between 0.4 and 2.5% (White P D, et al., Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy, BMC Neurol 2007, 7: 6). In the United States and the United Kingdom, four studies give an estimate of 0.2% to 0.7%, in other words, 200 to 700 cases per 100,000 people. In Japan, a prevalence of 1.5% was recorded. In general, prevalence estimates for CFS were between 0.5% and 2.5% in primary care centres, depending on the intensity of medical, psychiatric and laboratory evaluation (The Royal Australasian College of Physicians. Chronic Fatigue Syndrome. Clinical Practice Guidelines 2002).
The prognosis for recovery from CFS is extremely poor and at present there is no universal treatment which has been demonstrated to be an effective option for treating CFS (Hill N F, et al., Natural history of severe chronic fatigue syndrome, Arch Phys Med Rehabil 1999; 80(9): 1090-1094). Therefore, as things stand, the main therapeutic objective is based on alleviating the symptoms. Some of the treatments offered include: cognitive behavioural therapy, graduated exercise therapy, pharmacological intervention (such as antiviral, antidepressant, sedative, analgesic, anti-inflammatory and other drugs) and nutritional supplements. However, these interventions often do not produce the minimum benefit considered necessary in many patients with CFS (Afari N, et al., Chronic fatigue syndrome: a review, Am J Psychiatry, 2003; 160(2): 221-236/Rimes K A, et al, Treatments for Chronic Fatigue Syndrome, Occupational Medicine 2005: 5(1); 32-39). It is therefore clear that there is a need for effective medicines for the treatment of CFS.
CFS is a multisystemic disease of which the aetiology or triggering factor is not known, although there are various hypotheses as to the causal agents: genetic defects, abnormalities of the central nervous system, neuromuscular and metabolic irregularities, psychological factors, toxic agents, infections and immunological imbalances due to chronic activation of the immune system (Afari N, et al., Chronic fatigue syndrome: a review, Am J Psychiatry, 2003; 160(2): 221-236). Specifically, based on the chronically activated immune state, some authors suggested that the clinical and immunological abnormalities observed in CFS could include defects in the 2-5A defence pathway induced by interferons (Englebienne P, et al., Chronic Fatigue Syndrome. A Biological Approach, CRC Press LLC, 2002).
Interferons (IFNs) are proteins produced naturally by the immune system in response to external agents such as bacteria, viruses and parasites, and cancer cells. The two most significant products for IFN stimulation are the protein kinase R (PKR) and ribonuclease L (RNase L). PKR inhibits the translation of viral mRNA whereas RNase L shuts off dsRNA. The ultimate objective of both proteins is to induce the apoptosis of the infectious agents.
In 1994 Suhadolnik, et al. (Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome, Clin Infect Dis 1994; 18 (Suppl. I): S96-S104) discovered that the peripheral blood mononuclear cells (PBMC) of patients with CFS had hyperactive RNase L with a molar mass of 37 kDa, produced by the proteolysis of the native form of 83 kDa RNase L. Later, De Meirleir, et al. (A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome, Am J Med 2000; 108(2): 99-105) observed that the ratio between the concentration of the 37 kDa molecule and the 83 kDa molecule in PBMC was useful for differentiating patients with CFS from those suffering from FM or major depression.
Patients with CFS exhibit many symptoms which are characteristic of ion channel transport dysfunctions. The potential for ion channel interruption in patients with CFS was taken into account when it was determined that the RNase L inhibitor (RLI) belonged to the ABC superfamily of ion channel transporters. RLI deactivates RNase L by combining with the ankyrin domains present in RNase L. The elimination of the ankyrin domain during RNase L fragmentation, seen in patients with CFS, suggested that these ankyrin fragments may be capable of interacting and interrupting the normal functioning of the ion channels. A dysfunction of these transporters would explain many of the symptoms found in patients with CFS: nocturnal sweats, sarcoidosis, chemical hypersensitivity, macrophage dysfunction, immune system deficiency, disrupted monoamine transport, increased sensitivity to pain, Th2 dominance, abnormalities of the central nervous system, vision problems, loss of potassium in the muscles, transitory hypoglycaemia and depression (Englebienne P, et al., Interactions between RNase L, ankyrin domain and ABC transporters as a possible origin of pain, ion transport, CNS and immune disorders of chronic fatigue immune dysfunction syndrome, J Chronic Fatigue Syndrome 2001; 8 (3/4): 83-102).
Elastase, cathepsin-G and m-calpain are enzymes capable of causing the proteolysis or fragmentation of RNase L (Englebienne P, et al., Interactions between RNase L, ankyrin domain and ABC transporters as a possible origin of pain, ion transport, CNS and immune disorders of chronic fatigue immune dysfunction syndrome, J Chronic Fatigue Syndrome 2001, 8 (3/4): 83-102/Demetre E, et al., Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients, J Biol Chem 2002: 20; 277(38): 35746-35751). These three proteases are involved in the defence mechanisms against pathogenic agents and in the inflammatory processes, and they are therefore often found in abnormally high concentrations during an inflammatory response. In the case of CFS, it was found that patients suffering from this disorder usually had high concentrations of elastase (Demetre E, et al., Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients, J Biol Chem 2002: 20; 277(38): 35746-35751/Nijs J, et al. Chronic fatigue syndrome: exercise performance related to immune dysfunction, Med Sci Sports Exerc 2005; 37(10): 1647-1654).
Demetre E, et al. demonstrated that elastase has a significant role in the degradation of RNase L, when they proved that a specific inhibitor of elastase was capable of inhibiting, to a great extent, the proteolysis of RNase L in a PBMC culture from patients with CFS.
Faced with the need to find effective drugs for the treatment of CFS, the inventors undertook very extensive, in-depth investigations and tests which have resulted in the present invention, which is based on the use of alpha-1-antitrypsin (AAT) for the preparation of drugs for the treatment of CFS.